The administration of deferasirox in an iron-overloaded dialysis patient

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<ul><li><p>Letter to the Editor</p><p>The administration of deferasirox in aniron-overloaded dialysis patient</p><p>To the Editor:Iron overload has been implicated as a nontraditionalrisk factor for cardiovascular diseases in patients withchronic kidney disease (CKD) and end stage renaldisease (ESRD).1,2 Given this fact, iron overload not onlyoffers clinical prognostic value, but will be an emergingtherapeutic target in CKD and dialysis patients. Here, wepresent a case involving a dialysis patient with severehemochromatosis who underwent successful treatment.</p><p>Since January 2008, a 59-year-old male patient hadbeen suffering from an intractable malaise. He had ahistory of paroxysmal nocturnal hemoglobinuria (PNH)and received maintenance dialysis therapy for ESRD sinceSeptember 2007. The PNH was initially diagnosed in1984 and gradually became transfusion dependent. In the1990s, the frequency of transfusion was seasonal, andthen became monthly in the 2000s. The first biochemicalexamination in our hospital revealed serum iron levels tobe 181 mg/dL (normal 30180 mg/dL), total iron-bindingcapacity to be 192 mg/dL (normal 250450 mg/dL), trans-ferrin saturation to be 94.3%, and ferritin levels to be7420 ng/mL (normal 21.8274.66 ng/mL). After develop-ing into ESRD, the patient required frequent transfusionswith packed red blood cells (PRBC; 500 mL biweekly) inaddition to the aggressive use of an erythropoiesis-stimulating agent for refractory anemia to maintain hemo-globin levels at approximately 8.09.0 g/dL. Given thehistory of refractory anemia and regular componenttherapy accompanied by severe intractable malaise and asoaring serum ferritin level, a clinical diagnosis of chroniciron overload was made. Chelating therapy with deferox-amine (DFO, Desferal; Novartis Pharmaceuticals, Basel,Switzerland) was initiated in May 2008. One year later,</p><p>the patients serum ferritin concentration exceeded12,000 ng/mL, and was accompanied by severe exertionaldyspnea and chronic hepatitis. Abdominal magnetic reso-nance imaging (MRI) revealed a decreasing signal in boththe liver and the spleen (Figure 1). Given the poorresponse to DFO, an alternative chelating agent, defera-sirox (Exjade; Novartis Pharmaceuticals), was considereddespite it not being approved for the ESRD population ineither Taiwan or by the US Food and Drug Administration(FDA). After obtaining the patients consent, 750 mg(15 mg/kg/d) of deferasirox was administered daily sinceJuly 2009. The patients serum ferritin levels declinedsteadily to 3252 ng/mL under the maintenance dosage of500 mg/d (10 mg/kg/d) that was initiated in December2010 (Figure 2).</p><p>In this PNH patient with ESRD, renal anemia furtheraggravated the transfusion demand for this rare disorderthat is characterized by defective hematopoiesis.3 Ironoverload was therefore inevitable in our patient given themultiple and frequent blood transfusions, approximatingat least 300 units of PRBC (unit of blood = 250 mL) so</p><p>Correspondence to: Y.-M. Chen, MD, Department ofInternal Medicine, National Taiwan University HospitalYun-Lin Branch, Yun-Lin 640, Taiwan. E-mail:chenym@ntuh.gov.twPotential conflicts of interest. All authors: no conflicts.Funding: No funding sources.</p><p>Figure 1 Secondary hemochromatosis. Axial magnetic reso-nance imaging with the T2-weighted fast-recovery fastspin-echo (FRFSE) sequence demonstrated significant accen-tuated decreases in liver and spleen signal intensities.</p><p>Hemodialysis International 2012; :</p><p> 2012 The AuthorsHemodialysis International 2012 International Society for HemodialysisDOI:10.1111/j.1542-4758.2012.00704.x 1</p></li><li><p>far. Although the symptoms of secondary hemochroma-tosis are nonspecific, intolerable weakness, abdominalpain, and anorexia are symptoms that allowed the clini-cians to direct their attention to iron overload; this diag-nosis was supported by extremely high serum levels offerritin, transferrin saturation of &gt;45%, and typical ironoverload on liver MRI. The challenge that followed wasdetermining how to successfully conduct chelatingtherapy in a dialysis patient with extreme iron accumu-lation. Borrowing from the experience of treating dialysispatients suffering from aluminum overload, DFO wastitrated gradually from a dosage of 1040 mg/kg/weekand administered during a period of 1 year.4 However,no sign of clinical improvement was observed and serumferritin levels progressively increased to 12,123 ng/mL.Considering iron chelation therapy, deferasirox offeredan alternative option.5 Thus, we replaced the adminis-tration of intravenous DFO with that of oral deferasirox.We began with a dose of 15 mg/kg/d and slowly titratedthe dosage to a maximum of 30 mg/kg/d. The patientresponded well with a progressive decrease in serum fer-ritin levels during the follow-up period. Currently, undera daily dosage of 10 mg/kg/d, the patient remains freefrom iron overload symptoms, with serum ferritin levels</p><p>controlled at 30003500 ng/mL. Furthermore, ourpatient did not experience any significant complicationsfrom deferasirox administration, including skin rash,fever, or intolerable abdominal pain. It is also worthnoting that hypocalcemia, which is the only adverseeffect known to result from deferasirox use in a ESRDpatient, was also absent in our patient.6 This case dem-onstrates the effectiveness, safety, and tolerability ofdeferasirox administration in dialysis patients. Given thatdeferasirox may cause acute renal failure, creatinineclearance 2-fold theupper limit of normal are listed as contraindications byNovartis and the FDA.7 However, deferasirox has notbeen studied in patients with renal impairment. Itsmechanism of iron excretion is predominantly fecal, andboth deferasirox and its metabolites are primarilyexcreted in feces.7 Based on our experience, deferasiroxcan be hypothesized to be safe for patients with ESRDundergoing renal replacement therapy, for whom acuterenal failure is no longer a concern.</p><p>Manuscript received December 2011; revised March2012.</p><p>5000</p><p>550015000</p><p>Ferritin Deferasirox Deferoxamine(DFO)</p><p>3500</p><p>4000</p><p>4500</p><p>9000</p><p>12000</p><p>2000</p><p>2500</p><p>3000</p><p>6000</p><p>500</p><p>1000</p><p>1500</p><p>3000</p><p>0</p><p>500</p><p>0</p><p>Ferritinng/mL</p><p>Dosagemg*</p><p>Figure 2 Trends in serum ferritin levels and the dosages of deferoxamine and deferasirox administered from 2008 to 2010.*Axis scale of deferoxamine (DFO) is mg week and of deferasirox is mg per day.</p><p>Letter to the Editor</p><p>Hemodialysis International 2012; :2</p></li><li><p>Ching-Wei TSAI,1,2 Feng-Jung YANG,1,2</p><p>Chun-Chieh HUANG,3 Chin-Chi KUO,1,2</p><p>Yung-Ming CHEN1,21Department of Internal Medicine, National Taiwan University</p><p>Hospital Yun-Lin Branch, Yun-Lin, Taiwan;2Department of Internal Medicine, National Taiwan University</p><p>Hospital, Taipei, Taiwan;3Department of Medical Imaging, Far Eastern Memorial</p><p>Hospital, Taipei, Taiwan</p><p>REFERENCES1 Kletzmayr J, Horl WH. Iron overload and cardiovascular</p><p>complications in dialysis patients. Nephrol Dial Transplant.2002; 17(Suppl 2):2529.</p><p>2 Van Buren P, Velez RL, Vaziri ND, Zhou XJ. Iron overdose:A contributor to adverse outcomes in randomized trials of</p><p>anemia correction in CKD. Int Urol Nephrol. 2012;44:499507.</p><p>3 Rimola J, Martin J, Puig J, Darnell A, Massuet A. Thekidney in paroxysmal nocturnal haemoglobinuria: MRIfindings. Br J Radiol. 2004; 77:953956.</p><p>4 McCarthy JT, Milliner DS, Schmidt DF, Schniepp BJ, KurtzSB, Johnson WJ. Deferoxamine and coated charcoalhemoperfusion to remove aluminum in dialysis patients.Kidney Int. 1988; 34:804808.</p><p>5 Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effective-ness and safety of ICL670 in iron-loaded patients withthalassaemia: A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003; 361:15971602.</p><p>6 Yusuf B, McPhedran P, Brewster UC. Hypocalcemia in adialysis patient treated with deferasirox for iron overload.Am J Kidney Dis. 2008; 52:587590.</p><p>7 Hohneker JA. Exjade (deferasirox): Boxed warning. In:MedWatch: The FDA Safety Information and AdverseEvent Reporting Program; 2010.</p><p>Letter to the Editor</p><p>Hemodialysis International 2012; : 3</p></li></ul>